ABSTRACT
OBJECTIVE: Osteoarthritis (OA) drug development is hampered by a number of challenges. One of the main challenges is the apparent discordance between pain and structure, which has had a significant impact on drug development programs and has led to hesitance among stakeholders. Since 2017, the Clinical Trials Symposium (CTS) has been hosted under the Osteoarthritis Research Society International (OARSI) leadership. OARSI and the CTS steering committee yearly invite and encourage discussions on selected special subject matter between regulators, drug developers, clinicians, clinical researchers, biomarker specialists, and basic scientists to progress drug development in the OA field. METHOD: The main topic for the 2022 OARSI CTS was to elucidate the many facets of pain in OA and to enable a discussion between regulators (Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) and drug developers to clarify outcomes and study designs for OA drug development. RESULTS: Signs or symptoms indicative of nociceptive pain occur in 50-70% of OA patients, neuropathic-like pain in 15-30% of patients, and nociplastic pain in 15-50% of patients. Weight-bearing knee pain is associated with bone marrow lesions and effusions. There are currently no simple objective functional tests whose improvements correlate with patient perceptions. CONCLUSIONS: The CTS participants, in collaboration with the FDA and EMA, raised several suggestions that they consider key to future clinical trials in OA including the need for more precise differentiation of pain symptoms and mechanisms, and methods to reduce placebo responses in OA trials.
Subject(s)
Osteoarthritis, Knee , Osteoarthritis , Humans , Clinical Trials as Topic , Osteoarthritis/complications , Osteoarthritis/drug therapy , Osteoarthritis/diagnosis , Knee Joint/pathology , Pain/etiology , Pain/complications , Patient Reported Outcome Measures , Osteoarthritis, Knee/pathology , Treatment OutcomeABSTRACT
OBJECTIVES: The purpose of this study was to examine the humoral and cellular immune reactivity to adenoviral vector (AdhAQP1) administration in the human parotid gland over the first 42 days of a clinical gene therapy trial. METHODS: Of eleven treated subjects, five were considered as positive responders (Baum et al, 2012). Herein, we measured serum neutralizing antibody titers, circulating cytotoxic lymphocytes, and lymphocyte proliferation in peripheral blood mononuclear cells. Additionally, after adenoviral vector stimulation of lymphocyte proliferation, we quantified secreted cytokine levels. RESULTS: Responders showed little to modest immune reactivity during the first 42 days following gene transfer. Additionally, baseline serum neutralizing antibody titers to serotype 5-adenovirus generally were not predictive of a subject's response to parotid gland administration of AdhAQP1. Cytokine profiling from activated peripheral blood mononuclear cells could not distinguish responders and non-responders. CONCLUSIONS: The data are the first to describe immune responses after adenoviral vector administration in a human parotid gland. Importantly, we found that modest (2-3 fold) changes in systemic cell-mediated immune reactivity did not preclude positive subject responses to gene transfer. However, changes beyond that level likely impeded the efficacy of gene transfer.
Subject(s)
Adenoviridae/immunology , Antibodies, Neutralizing/blood , Genetic Vectors/immunology , T-Lymphocytes, Cytotoxic , Aged , Aquaporin 1/genetics , Cell Proliferation , Cytokines/blood , DNA, Complementary/genetics , Female , Genetic Therapy , Humans , Immunity, Cellular , Lymphocyte Count , Male , Middle Aged , Parotid Gland/virology , T-Lymphocytes, Cytotoxic/physiologyABSTRACT
We evaluated late effects of AdhAQP1 administration in five subjects in a clinical trial for radiation-induced salivary hypofunction (http://www.clinicaltrials.gov/ct/show/NCT00372320?order=). All were identified as initially responding to human aquaporin-1 (hAQP1) gene transfer. They were followed for 3-4 years after AdhAQP1 delivery to one parotid gland. At intervals we examined salivary flow, xerostomic symptoms, saliva composition, vector presence and efficacy in the targeted gland, clinical laboratory data and adverse events. All displayed marked increases (71-500% above baseline) in parotid flow 3-4.7 years after treatment, with improved symptoms for ~2-3 years. There were some changes in [Na+] and [Cl-] consistent with elevated salivary flow, but no uniform changes in secretion of key parotid proteins. There were no clinically significant adverse events, nor consistent negative changes in laboratory parameters. One subject underwent a core needle biopsy of the targeted parotid gland 3.1 years post treatment and displayed evidence of hAQP1 protein in acinar, but not duct, cell membranes. All subjects responding to hAQP1 gene transfer initially had benefits for much longer times. First-generation adenoviral vectors typically yield transit effects, but these data show beneficial effects can continue years after parotid gland delivery.
Subject(s)
Aquaporin 1/genetics , Genetic Therapy/adverse effects , Xerostomia/therapy , Adenoviridae/genetics , Aquaporin 1/metabolism , Chlorides/metabolism , Genetic Vectors/genetics , Humans , Middle Aged , Radiotherapy/adverse effects , Salivary Glands/metabolism , Sodium/metabolism , Xerostomia/etiologyABSTRACT
Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder caused by mutations in the WAS gene. Glomerulonephritis is a frequent complication, however, histopathological data from affected patients is scarce because the thrombocytopenia that affects most patients is a contraindication to renal biopsies. We found that WASp-deficient mice develop proliferative glomerulonephritis reminiscent of human IgA nephropathy (IgAN). We examined whether increased aberrant IgA production is associated with the development of glomerulonephritis in WASp-deficient mice. Serum IgA and IgA production by splenic B cells was increased in WASp-deficient mice compared to wild-type (WT) mice. A lectin-binding study revealed a reduced ratio of sialylated and galactosylated IgA in the sera from old WASp-deficient mice. Circulating IgA-containing immune complexes showed significantly higher titers in WASp-deficient mice compared to WT mice. These results indicate that the increased IgA production and aberrant glycosylation of IgA may be critically involved in the pathogenesis of glomerulonephritis in WAS.
Subject(s)
Glomerulonephritis, IGA/immunology , Immunoglobulin A/metabolism , Wiskott-Aldrich Syndrome Protein/deficiency , Wiskott-Aldrich Syndrome/immunology , Animals , B-Lymphocytes/immunology , Disease Models, Animal , Glomerulonephritis, IGA/metabolism , Glomerulonephritis, IGA/pathology , Glycosylation , Humans , Immunoglobulin A/blood , Mice , Mice, Knockout , Spleen/immunology , Thrombocytopenia/metabolismABSTRACT
Single nucleotide polymorphisms in the STAT4 gene have recently been shown to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Primary Sjögren's syndrome (pSS) is a related autoimmune disease thought to have a pathogenesis similar to these diseases. To test the hypothesis that the variant haplotype of STAT4 seen in RA and SLE is also associated with pSS, we genotyped rs7574865, the most strongly disease-associated SNP in the variant STAT4 haplotype, in 124 Caucasian pSS subjects and compared them to 1143 Caucasian controls. The disease-associated T allele was more common in chromosomes of the pSS patients (29.6%) than in controls (22.3%), leading to a P-value for association of 0.01. These results implicate polymorphisms in the STAT4 gene in the pathogenesis of pSS.
Subject(s)
Polymorphism, Single Nucleotide/genetics , STAT4 Transcription Factor/genetics , Sjogren's Syndrome/genetics , Adult , Aged , Female , Gene Frequency , Genotype , Haplotypes/genetics , Humans , Male , Middle Aged , White People/geneticsABSTRACT
Many rheumatologic disorders, most notably Sjögren's syndrome, are associated with dental complications and in some cases oral diseases may trigger or drive connective tissue disease. During the past three decades the treatment in rheumatology was revolutionized by the introduction of disease-modifying anti-rheumatic drugs. Advances in our understanding of the pathogenesis of rheumatic diseases have led to the discovery of critical mechanisms of inflammation and autoimmunity and the invention of new target-specific biologic agents. In this review, we will summarize the current state of biologic therapies in rheumatology and discuss the implications of these on oral health and disease.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Immunologic Factors/therapeutic use , Rheumatic Diseases/therapy , Sjogren's Syndrome/therapy , Abatacept , Animals , Antibodies, Monoclonal/immunology , B-Cell Activating Factor/immunology , Humans , Immunoconjugates/immunology , Interferon-alpha/immunology , Interleukins/immunology , Lymphocyte Activation , Rheumatic Diseases/drug therapy , Rheumatic Diseases/immunology , Sialic Acid Binding Ig-like Lectin 2/immunology , Sjogren's Syndrome/drug therapy , Tumor Necrosis Factor-alpha/immunologyABSTRACT
OBJECTIVE: To determine the frequency of liver function tests (LFT) abnormalities associated with methotrexate (MTX) use in the treatment of rheumatoid arthritis (RA). METHODS: A retrospective chart review for demographic information, RA-specific history, medication history, complications of therapy, results of all available blood tests (specifically aspartate aminotransferase (AST), alanine aminotransferase (ALT), complete blood count (CBC), albumin, creatinine), and liver biopsy reports was conducted for RA patients, who were currently using or have used MTX in the past. RESULTS: A total of 2791 LFTs were performed among 182 RA patients with 94 abnormal results. 152 patients (83.5%) with 2007 LFT evaluations demonstrated no abnormal results, compared with 30 patients (16.5%) who had at least one abnormal LFT in 784 tests. Twenty-two of the 30 patients with at least one LFT abnormality (73.3%) continued treatment despite the elevation without further evaluation or change in therapy, and subsequent LFT assessments were within normal limits. 128 patients (70.3%) remained on MTX at the time of our study. The most common reason for discontinuation was inadequate response. CONCLUSIONS: MTX appears to be associated with very few clinically significant hepatic side effects. In view of these data, consideration as to revision of the current MTX monitoring guidelines in the direction of less frequent monitoring, especially in patients with no risk factors for liver disease, may be considered.
Subject(s)
Antirheumatic Agents/adverse effects , Arthritis, Rheumatoid/drug therapy , Chemical and Drug Induced Liver Injury , Liver/drug effects , Methotrexate/adverse effects , Adolescent , Adult , Aged , Aged, 80 and over , Arthritis, Rheumatoid/complications , Female , Humans , Liver/pathology , Liver Diseases/blood , Liver Diseases/pathology , Liver Function Tests , Male , Middle Aged , Retrospective StudiesABSTRACT
Two cases with typical clinical and histological manifestations of Whipple's disease were reported. Peroral jejunal biopsies were studied in the florid stage and during remission achieved by tetracycline therapy. A complete absence of immunoglobulin-containing cells (Ig-CC) and an increased number of mast cells in the mucosa were established in one of the cases. A 5-fold decrease of the mucosal Ig-CC was found by immunofluorescent morphometry in the second case. An increased Ig-CC number and histological restitution of the mucosa were shown in the first case during remission, whereas histological alterations and decreased Ig-CC number persisted in the second case despite of clinical improvement. The HLA-locus B27 was not available in the reported cases.
Subject(s)
Intestinal Mucosa/pathology , Whipple Disease/diagnosis , Female , Fluorescent Antibody Technique , Humans , Immunoglobulins/metabolism , Jejunum/pathology , Macrophages/ultrastructure , Male , Microvilli/ultrastructure , Middle Aged , Whipple Disease/pathologyABSTRACT
A total of 45 patients were studied: seven with gluten enteropathy and 38 with chronic unspecific enteritis. Histological and immunefluorescent studies were performed and to a part of the cases--enzymatic and electron-microscopic investigations of the jejunal mucosa. An increased number of immuneglobulin -secreting cells was established in the non-treated patients with gluten enteropathy, growing with age. In the cases with chronic unspecific enteritis with a manifested clinic, a tendency to decrease of the number of IgSC was observed, with growing percentage of IgG-SC and the values of the secretory IgG. There was no correlation between the intraepithelially located lymphocytes and those in the chorion, as well as between the duration of the disease, number and percentage distribution of Ig-SC.
Subject(s)
Antibody-Producing Cells/immunology , Celiac Disease/immunology , Enteritis/immunology , Immunoglobulins/analysis , Intestine, Small/immunology , Chronic Disease , Fluorescent Antibody Technique , Humans , Intestinal Secretions/immunology , Jejunum/immunologyABSTRACT
The results from the clinical, morphological and enzymatic studies are reported upon the jejunal mucosa and the effect of a gluten-free diet among a group of 60 patients with gluten enteropathy and 5 patients with idiopathic steatorrhea. The significance of light microscopic and electronmicroscopic studies are discussed in details in making the diagnosis, differential diagnosis and assessment of the results from the treatment of gluten enteropathy.